tbuckley/cabot-search huggingface dataset:
P10.07.B Differential YAP activity in human glioblastoma tumorspheres
Authors: E Kim, Y Oh, S Kang
Journal: Neuro-Oncology (2022)

Abstract Background Although glioblastoma (GBM) is the most common primary brain tumor, the best available treatment options are still associated with poor prognosis. Recently, the Hippo/YAP signaling pathway has been emerged as an important driver of GBM. Nevertheless, extensive studies have not yet been focused on the importance of phosphorylation event in regulating endogenous YAP activity in GBM. Here, we sought to elucidate that the modulation and stabilization of YAP/TAZ in Hippo pathway promotes GBM progression. Material and Methods Expression patterns of YAP1, TAZ, CTGF, TEAD4 and LATS1 mRNA were confirmed in human normal and GBM tissue, and patient survival according to YAP1 expression was confirmed in TCGA and Severance cohort. The YAP1 expression patterns in several TSs were classified into SOH and AH according to transcriptome analysis and western blot. For each classified TSs, the characteristics of SOH and AH were comparatively analyzed through immunoprecipitation, nucleus fraction, TEAD4 luciferase assay, and confocal analysis. The effect of YAP1 knockdown/out and overexpression in SOH and AH TSs were measured by WST/ATP analysis, 3D invasion and neurosphere formation, and western blot. In addition, the drug reactivity of SOH and AH TSs was examined by treatment with the YAP1 inhibitors Peptide17 and verteporfin, and the effects of Peptide17, verteporfin and YAP1-shRNA were examined in in-vivo xenograft model. Results YAP1 mRNA levels including TAZ, CTGF, TEAD4 and LATS1 were higher in GBM than in normal tissues. Through transcriptome analysis and western blot, TS can be divided into SOH and AH groups according to the expression level of CTGF, but not YAP1 level. In the case of SOH TS, the binding of TEAD4 was strong in immunoprecipitation, the ratio of YAP1 was higher in the nucleus in the nucleus fractionation and confocal analysis, and the luciferase activity of TEAD4 was high in the TEAD4 luciferase assay. On the other hand, in the case of TS of AH, the opposite trend was observed. When YAP1 was knocked down or out, the proliferation, invasion, and stemness of TS tended to be decrease more in SOH TS than in AH TS, and SOH TS showed more sensitive drug response even in Peptide17 and Verteporfin treatment. In the case of YAP1 overexpression, the opposite trend was observed in SOH TS. In the in-vivo xenograft model, injection of Peptide17, verteporfin, and YAP1-shRNA showed a tendency to increase the survival rate of mice. Conclusion The association of YAP has been described in several cancers, but there has been no study comparing GBM TS by YAP expression and classifying it at the functional level. Now, for the first time, we show that the characteristics of GBM TS can be predicted according to the expression value of YAP, respectively, and YAP is expected to be applied as an important prognostic factor for GBM treatment in the future.
P17.07.A Metronomic temozolomide therapy in heavily pretreated patients with recurrent glioblastoma: a large mono-institutional retrospective study
Authors: A Bosio, M Padovan, M Caccese, G Cerretti, V Zagonel, G Lombardi
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Despite advances in surgical and first-line treatment, all pts relapse. The aim of this study is to evaluate the benefit of metronomic Temozolomide (mTMZ) for recurrent GBM. Material and Methods All pts treated at Veneto Institute of Oncology from September 2013 to March 2021 were retrospectively reviewed. Major inclusion criteria were: first-line therapy with Stupp protocol, relapse after first or subsequent line of therapy, treatment with mTMZ schedule (50mg/m2 continuously), hystologically confirmed diagnosis of GBM. RANO criteria and CTCAE v 5.0 were used for response and toxicity assessment. Results 120pts were enrolled. Median follow-up was 15.6ms. Median age was 59ys (range 18-81), ECOG-PS was 0-2 in 107pts (89%) and 3 in 11 (9%). MGMT was methylated and IDH mutated in 66 of 105 (62%) and in 9 of 106 (8%) evaluable pts, respectively. Median number of prior lines of treatment was 2 (range 1-7) and 41% of pts received the therapy beyond the third line. Median time between the last standard maintenance TMZ (sTMZ) cycle and the mTMZ administration was 6ms (range 1-50) and 40% of pts started mTMZ after 3ms from sTMZ. All pts were evaluable for response: 3 (2%) and 48 (40%) showed PR and SD. mOS from the start of mTMZ was 5.4ms (95% CI 4.3-6.4), mPFS was 2.6ms (95% CI 2.3-2.8). At univariate analysis, MGMTmet and MGMTunmet pts had a mOS of 5.6 and 4.4ms (p=0.03); mOS for patients with ECOG-PS &amp;gt; or ≤2 was 2.3 and 6.0ms (p&amp;lt;0.001); number of prior lines of therapies, time between sTMZ and mTMZ and age were not significant. At multivariate analysis, MGMT methylated status (HR=2.3, 95% CI, p=0.004) and ECOG-PS (HR=0.5, 95% CI, p=0.017) remained statistically significant for PFS, while ECOG-PS (HR=0.4, 95% CI, p=0.001) was the only factor significantly associated with OS. The most common grade 3-4 hematologic toxicities were lymphopenia (10%) and thrombocytopenia (3%). Grade 3-4 nonhematologic toxicities were uncommon. Conclusion Rechallenge with mTMZ can be a well tolerated treatment option for recurrent GBM, even in heavily pretreated pts. Pts with MGMTmet and good ECOG-PS might report the major benefit.
P11.55.B Postoperative MRI is able to detect an unexpected residual tumor after surgery of brain metastases: experience from 5 specialized centers
Authors: B Kiesel, J Kerschbaumer, R Prihoda, M Borkovec, S Thakur, P Mercea, D Feucht, A Steindl, A S Berghoff, J Furtner, J Leitner, A Romagna, C Schwartz, H Stefanits, F Marhold, T Rötzer, M Preusser, C Freyschlag, G Widhalm
Journal: Neuro-Oncology (2022)

Abstract Background Brain metastases (BM) constitute the most common central nervous system tumors. The treatment options of BM consist of surgery, radiotherapy, radiosurgery, chemotherapy, and immunotherapy. Regarding surgery in BM, the extent of resection (EOR) represents a crucial factor for patient prognosis. However, first studies using postoperative MRI demonstrated that an unexpected residual tumor after surgery of BM is not uncommon despite these tumors were considered to be well-demarcated. The aim of this study was thus to investigate in a large cohort including multiple neurosurgical centers the EOR following BM resection, potential risk factors for incomplete resection and postsurgical follow-up data. Material and Methods In the current retrospective study conducted at 5 specialized neurosurgical centers in Austria, we included patients with BM resection and available postoperative MRI. The EOR following BM resection was determined by postoperative MRI (complete vs incomplete resection). Additionally, the data on the intraoperative judgement of the EOR of the performing neurosurgeon were collected. Moreover, potential factors for incomplete resection including tumor localization, tumor volume, primary tumor, pattern of contrast media enhancement on imaging and tumor eloquence were investigated. Finally, the rate of local progression of BM after initial surgery was analyzed in the follow-up period and overall survival data were collected. Results Altogether, 548 patients with 649 surgically treated BM were included. According to postoperative MRI, complete resection was achieved in 407 (66%) of 649 BM and incomplete resection in 176 (29%) of 649 BM. Misjudgment of the EOR by the neurosurgeon was found in 25% of cases and resulted in an unexpected residual tumor which was evident on postoperative MRI in 122 (22%) BM. Preoperative tumor volume was significantly larger in incompletely resected BM. Moreover, local progression was significantly more common in cases with incompletely resected BM and was also associated with shorter overall survival. Conclusion Our data of this study including multiple centers indicate that postoperative MRI is capable to detect a relatively high rate of unexpected residual tumors following resection of BM. Since local progression was more common in BM with residual tumors and this was associated with shorter survival, special attention should be paid to achieve a complete tumor resection.
P18.03.B Long term effects of therapeutic embolization of radiographically suspected meningiomas regarding tumour- and necrosis volume as well as patients' symptoms
Authors: M Pedersen, T Eibl, A Nania, H Voit-Höhne, M Schrey, H Steiner, M Holtmannspötter
Journal: Neuro-Oncology (2022)

Abstract Background Preoperative embolization of radiographically suspected intracranial meningiomas is performed to reduce intraoperative blood loss and to facilitate resection. However, there is paucity of evidence examining the effect of embolization as a sole intervention on the tumor volume and the patient's neurocognitive symptoms. The objective of this study was to investigates the influence of therapeutic embolization on tumor- and necrosis volume and neurocognitive symptoms in absence of surgical intervention. Material and Methods Between January 2019 and June 2021, 4 patients (median age 82, 1 female) with 5 radiographically suspected intracranial meningiomas, underwent endovascular embolization with liquid embolizate and coils, without subsequent surgery. Indication for embolization was history of previous multiple surgery contraindicating further surgical intervention or patients will. Neurological status (on admission, discharge from hospital and 5 months after embolization), medical history, medication, MRI (location, tumor- and necrosis volume, development of edema, complications), DSA (extent of embolization, arterial supply) and procedural complications were recorded. In 3 patients with 4 tumors, an MRI scan was performed. The calculation of tumor- and necrosis volume was done manually with a semiautomatic segmentation tool. One patient with one tumor received CT scans due to a cardiac pacemaker and was therefore excluded from volumetric analysis. Results The average tumor volume was 44,83 ± 13,82 cm3 on admission, 45,33 ± 16,3 cm3 5 days after embolization (+1%) and 39,93 ± 29,39 cm3 (-11%) after 5 months. The average necrosis diameter was 41,76 ± 9,33 mm after 5 days and 6,05 ± 6,43 mm after 5 months. The perifocal oedema decreased in 2/3 Patients. Tumor blood supply was via 2,4 ± 1,34 vessels, 1,2 ± 0,45 vessels were embolised. On admission, 3 patients showed neurocognitive symptoms. At discharge and in the follow-up, in 2 patients the symptoms had improved, one patient experienced a complete symptom regression. In one patient the embolization was complicated by dissection of the middle meningeal artery. The same patients perifocal oedema increased in the further clinical course with accompanying deterioration of the pre-existing hemiparesis from moderate to severe. Supported with dexamethasone medication, the oedema and symptoms declined to a mild residual paresis. None of the patients developed a long-term neurocognitive deficit related to embolization. Conclusion Therapeutic endovascular embolization of radiographically suspected intracranial meningiomas reduced the tumor volume and led to long-term improvement of pre-existing neurocognitive symptoms. In the future, these effects should be verified in larger studies.
P06.07.A Natural killer cells lyse glioblastoma stem cells and increase their sensitivity to chemotherapy
Authors: B Breznik, M Ko, P Chen, E Senjor, B Majc, M Novak, A Habič, A Jewett
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is the most common and lethal brain tumor in the adult population and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. In this study, we aimed to explore the therapeutic potential of allogeneic highly activated super-charged natural killer (NK) cells in glioblastoma. Material and Methods Chromium release- and calcein release-based cytotoxicity assays, ELISA, ELISPOT, and multiplex cytokine assays were used to determine NK cell cytotoxicity against glioblastoma stem cells (GSCs) and secretion of cytokines. Cell surface marker expression using flow cytometry and cell growth in vitro and in vivo were measured to determine GSC phenotype. NK cell killing and penetration in 3D were measured using confocal microscopy of GSC tumorospheres. Results Super-charged NK cells efficiently lysed patient-derived GSCs in 2D and 3D models potentially reversing the immunosuppression observed in patients. NK-cells secreted IFN-γ, upregulated GSC surface expression of CD54 and MHC class I and increased sensitivity of GSCs to chemotherapeutic drugs. Co-localization of NK cells with GBM cells in perivascular niches in glioblastoma tissues and their direct contact with GSCs in tumorospheres suggests their ability to infiltrate glioblastoma tumors and target GSCs. Conclusion Allogeneic super-charged NK cells appear to be a potential therapeutic approach for glioblastoma by selectively killing therapy-resistant cancer stem cell population, increasing their immune-related surface markers and enhancing their sensitivity to chemotherapy. Due to GSC heterogeneity and plasticity personalized immunotherapeutic strategies should be developed to effectively target glioblastomas.
P15.10.B A multicenter phase 3 trial in progress: diagnostic performance of18F-fluciclovine PET for the detection of recurrent brain metastases after radiation therapy (REVELATE)
Authors: S T Chao, A Chaglassian, N Tainer, E J Teoh
Journal: Neuro-Oncology (2022)

Abstract Background Following treatment of brain metastases, which can affect up to 40% of patients with cancer, patients will typically be closely monitored with serial brain magnetic resonance imaging (MRI) owing to the high likelihood of recurrence. The recommended follow-up modalities (CE-T1-weighted and FLAIR/T2-weighted MRI) have poor specificity, meaning that differentiation of true disease from treatment-related changes such as radiation necrosis can be difficult. Recent pilot studies have reported amino acid PET radiopharmaceutical, 18F-fluciclovine, to be potentially useful in discriminating brain tumor recurrence from treatment-related changes. This may potentially help physicians to make confident diagnoses and inform subsequent treatment plans. Material and Methods REVELATE (NCT04410133) will evaluate the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for the detection of recurrent brain metastases in patients for whom MRI is equivocal. This multicenter, phase 3, prospective, open-label trial aims to enroll approximately 150 subjects from across 19 US sites with solid tumor brain metastases who have undergone radiation therapy, if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures (either biopsy/neurosurgical intervention or clinical follow-up). Patients will undergo 18F-fluciclovine PET &amp;lt;42 days after the equivocal MRI and 1-21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Results The primary endpoint of REVELATE is the subject-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for detection of recurrent brain metastases. Further objectives include evaluation of the lesion-level diagnostic performance, inter-reader and intra-reader agreement, and safety evaluations. Conclusion This ongoing phase 3 study will provide efficacy and safety data for the use of 18F-fluciclovine for the detection of recurrent brain metastases. Enrolment began in October 2020 and the trial is active but not recruiting at the time of submission.
P11.64.A Long-term follow up and translational data from the ReoGlio phase Ib trial of GM-CSF and intravenous pelareorep (Reovirus) alongside standard of care in GBM
Authors: S Short, J Kendall, E West, A Chalmers, C McBain, A Melcher, F Collinson, R Phillip, S Brown, A Samson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND We previously reported safety data from a phase Ib, open-label study of intravenous oncolytic virus pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed glioblastoma confirming that the combination is well tolerated. We now report on long-term follow up and analysis of translational samples from tumour and blood in a subset of patients. METHODS 15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and intravenous pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following a protocol amendment we also collected survival data in all patients up to August 2021. Serial blood samples were taken from three patients, at baseline, during chemoradiotherapy and in the first adjuvant cycle. Peripheral blood mononuclear cells were analysed for immune checkpoint expression by flow cytometry, RNAseq gene expression and T-cell receptor clonality, whilst plasma cytokines were quantified by Luminex. RESULTS This combination was well tolerated with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months in dose level 1 and 16.1 months in dose level 2, median OS for all patients was 13.1 months. The 24-month survival estimate for all patients was 25.0%, 16.7% for dose level 1 and 33.3% for dose level 2. One patient in dose level 1 remains alive at 43 months post registration without further treatment. Laboratory data showed that pelareorep infusion resulted in inflammatory cytokine and chemokine secretion, immune checkpoint modulation, and upregulation of inflammatory pathways. There was also increased peripheral clonal tumour-specific T-cell proliferation following pelareorep infusion. CONCLUSION Although based on small numbers, these long-term follow up data suggest this may be an active combination in a subset of GBM patients. Translational data confirm that pelareorep potentially activates tumour-targeting immune pathways in GBM, with consequential immune checkpoint modulation. These data support a combination clinical trial of pelareorep, radiotherapy and immune checkpoint blockade in GBM.
P10.04.A The development of a potent, tumour-specific heptamethine cyanine dye-palbociclib conjugate with novel mechanisms of action for the treatment of glioblastoma
Authors: E A Cooper, P J Choi, P Schweder, J Correia, C Turner, R Faull, W A Denny, M Dragunow, J Jose, T I Park
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-cancer agents for brain tumours is challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery Material and Methods We conjugated palbociclib, a cyclin-dependent kinase 4/6 inhibitor to the HMCD, MHI 148 for the treatment of GBM. Patient-derived GBM cell lines were established from surgically resected biopsy GBM tissue. Results High-throughput drug screening revealed an almost 100-fold increase in cytotoxicity of the palbociclib-MHI 148 conjugate compared to palbociclib alone. Moreover, the palbociclib-MHI 148 conjugate was synergistic with radiation, but not with temozolomide. Further analysis revealed the palbociclib-MHI 148 conjugate was superior to other cyclin-dependent kinase inhibitors in vitro. The shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI 148 prompted further investigation. We revealed that palbociclib-MHI 148-dependent inhibition of cell-cycle progression resulted in increased DNA damage. This preceded increased transcription of key extrinsic apoptosis genes and caused a time-dependent upregulation of TNFR1 endocytosis-dependent cell death signalling. Notably, inhibition of endocytosis and siRNA knockdown of TNFR1 prevented palbociclib-MHI 148-induced cell death. Conclusion: These results highlight a novel mechanism of action of palbociclib when conjugated to MHI-148 that induced autocrine-driven TNFR1-mediated apoptosis. In addition, we highlight the potential application of HMCDs in repurposing tyrosine kinase inhibitors, to overcome the current limitations preventing the expansion of second-line treatment options for GBM.
P08.06.A Work resumption following lower-grade glioma surgery: a multicenter cohort study
Authors: I O Kommers, M N G van Genderen, R S Eijgelaar, M G Witte, Y de Haan, S Ille, E Mandonnet, S M Krieg, F Barkhof, P C de Witt Hamer
Journal: Neuro-Oncology (2022)

Abstract Background Patients with lower-grade glioma (LGG) are often of working age. For LGG patients post-surgical work resumption is at risk from treatment including resective surgery. However, little is known on determinants of returning to work. In this study we examined determinants of post-surgical work resumption after nine months using patient- and tumor-related characteristics, such as tumor and resection cavity locations. Material and Methods This retrospective multicenter cohort study included adults with supratentorial WHO grade II and III gliomas who underwent a first-time surgery in Paris, Munich or Amsterdam between 2011 and 2016. Patient-related characteristics included age, sex, patient condition, received treatments, classification of work type and skill level. Presurgical tumors and postsurgical resection cavities were manually segmented on MRI and registered to standard brain space. These segmentations were mapped to Schaefer, XTRACT and Harvard-Oxford atlas parcellations of cortical, white matter and grey nuclei structures. Predictors of postsurgical return to work were examined in multivariable logistic regression and Bayesian hurdle regression models. Results The cohort consisted of 219 patients. Before surgery 192 (88%) patients were able to work, and after surgery 119 (62%) resumed work. Independent predictors of returning to work were male sex (OR = 3.21, CI = 1.44 - 7.46, p = 0.005) and lower age (per 1 year older, OR = 0.96, CI = 0.92 - 0.99, p = 0.029). No associations were found between work resumption and locations of the tumor or resection cavity. Conclusion Many patients are able to work before and many return to work after first-time LGG surgery. Inability to resume work is exclusively associated with patient-related characteristics and not with tumor or resection locations. This novel information may inform patient counseling.